Use of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas (NFitor)

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Patients with the genetic disorder neurofibromatosis Type 1 (NF1) are at increased risk of developing tumors of the central and peripheral nervous system. These include plexiform neurofibromas. The conventional treatment of these internal plexiform neurofibromas is surgery. This surgery can be possible on a single and limited tumor. On the other hand these tumors are often surgically intractable due to their multiplicity and their infiltrating characteristics Increased activity of mammalian target of rapamycin(mTOR) protein is seen in neurofibromas. mTOR inhibitor rapamycin , or its derivatives such as everolimus may slow or stop tumor growth in patients with NF1.

Objectives:

Primary objectives To determine whether everolimus has an effect on the volume of surgically intractable and life-threatening internal plexiform neurofibromas in patients with neurofibromatosis 1.

Secondary objectives To determine whether everolimus has an effect on the number and the volume of cutaneous neurofibromas; to determine whether everolimus modify the signaling pathways in cutaneous neurofibromas.

Eligibility:

- Adults with neurofibromatosis type 1 with at least one internal plexiform neurofibroma, life-threatening or causing significant morbidity through compression of organs. This or these internal plexiform neurofibroma(s) should be intractable by surgery.

Design:

An open-label, single arm, non-randomized, single stage phase IIa study. Baseline phase: Baseline evaluations will be performed within 2 weeks, and up to a maximum of 4 weeks for specific exams, before the first dose of study drug.

Treatment phase/duration of treatment: All patients will be treated with RAD001 10 mg p.o daily dose for one year except in case of unacceptable toxicity, death, or discontinuation from the study for any other reason.

Follow-up phase: All patients will have two follow-up visits scheduled at 18 and 24 months after the first dose of the study drug to follow for adverse events (AEs) and serious adverse events (SAEs) that may have occurred after discontinuation from the study and for internal plexiform neurofibromas assessment.

Radiological review: All Magnetic Resonance Imaging (MRIs) obtained at baseline, during the treatment period and the follow-up period will be reviewed by the Neuroradiologist of the study.

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Ages Eligible for Study:

18 Years to 60 Years (Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Clinical diagnosis of NF1, according to NIH criteria, with internal plexiform neurofibroma (PN) and at least 1 of criteria for NF1:

6 or more café-au-lait spots Freckling in the axilla or groin Optic glioma 2 or more Lisch nodules Distinctive bony lesion

1-degree relative with NF1

At least 1 inoperable PN(s) that has/have the potential to cause significant morbidity: Paravertebral lesions that could compromise the spinal cord Head and neck lesions that could compromise the airway or great vessels Brachial or lumbar plexus lesions that could cause nerve compression and loss of function Lesions that could result in major deformity (e.g., orbital lesions) or significant cosmetic problems Lesions of the extremity that cause limb hypertrophy or loss of function Painful lesions

Complete resection of a PN with acceptable morbidity is not feasible OR patient refuses surgery OR the number of PNs leads to not feasible surgery according to the steering committee's site

Women of childbearing potential must have had a negative serum pregnancy test within 7 days and a negative urine pregnancy test within 72 hours prior to the administration of RAD001 start and must use an effective birth control method.

Men should use condoms and their partner(s) use an effective birth control method

A written informed consent obtained

Exclusion Criteria:

Patients who/with:

have previously received mTOR inhibitors

a known hypersensitivity to RAD001 or other rapamycin or to its excipients

receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent. (Dose equivalent to 10 mg/day of methylprednisone), topical steroids or organotherapy for bilateral adrenalectomy are acceptable

a known history of HIV seropositivity

acute viral hepatitis

autoimmune hepatitis

with an active, bleeding diathesis. Patients may use coumadin or heparin preparations

have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation

have a history of another primary malignancy ≤3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix

Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Oral contraceptives are not acceptable alone

a contraindication to MRI

are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study treatment start